Page 45 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 26 of 33

Table 4 The investigated outcomes of the ongoing clinical trials using MSCs and MSC-derived exosomes to treat COVID-19 patients
(Continued)
Clinical trial Primary Outcome Measure Secondary Outcome Measure
identifier
Incidence of serious adverse events (SAEs) [time frame, 28 2. Respiratory compliance (Crs) [time frame, days 4, 7, and 14].
days]. 3. Oxygenation index [time frame, days 4, and 14].
4. Ventilation and pulmonar function [time frame, 28 and 90
days].
NCT04345601 Treatment-related serious adverse events [time frame, 28 days N.A.
post cell infusion].
Change in clinical status at day 14 [time frame, 14 days post
cell infusion].
NCT04361942 Proportion of patients who have achieved withdrawal of Proportion of patients who have achieved clinical response (0–
invasive mechanical ventilation [time frame, 0–7 days]. 7 days) and radiological responses (0–28 days).
Mortality rate [time frame, 28 days].
NCT04333368 Respiratory efficacy evaluated by the increase in PaO 2 /FiO 2 1. Lung injury score, Oxygenation index, In-hospital mortality,
[time frame, from baseline to day 7]. mortality, ventilator-free days, proportion of PaO 2 /FiO 2 > 200,
cumulative use and duration of sedatives and neuromuscular
blocking agents, ICU-acquired weakness and delirium,
treatment-induced toxicity rate and adverse events up to day
28.
2. Quality of life at one year (EQ. 5D-3L quality of life question-
naire) [time frame, at 6 months and 12 months]
3. Measurements of plasmatic cytokines (IL1, IL6, IL8, TNF-
alpha, IL10, TGF-beta, sRAGE, Ang2) level [time frame, At day 1,
3, 5, 7 and 14].
4. Anti-HLA antibodies plasmatic dosage [time frame, from
baseline to day 14, and at 6 months].
NCT04389450 Number of ventilator-free days [time frame, 28 days]. 1. All-cause mortality [time frame, 28 days]
2. Duration of mechanical ventilation [time frame, 8 weeks].
NCT04367077 Ventilator-free days, safety and tolerability as measured by the 1. All-cause mortality [time frame, Day 60]
incidence of treatment-emergent adverse events [time frame, 2. Ranked hierarchical composite outcome of alive and
day 0–28]. ventilator-free [time frame, Day 28].
3. Ventilator-free days [time frame, day 0–60].
PEEP positive end-expiratory airway pressure, AEs/SAEs adverse events and severe adverse events, CRP C-reactive protein, LDH lactate dehydrogenase. APACHE II is
a prognostic score based on 12 different items obtained in the first 24 h of ICU admission. It ranges from 0 to 71 points. A higher score is associated with higher
mortality. TRAEIs, Pre-specified treatment-related adverse events of interest; NEWS2, National Early Warning Score 2 Score; NEWS: respiration rate, oxygen
saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness; SOFA, respiration, coagulation, liver, cardiovascular,
central nervous system, and renal

mainly attributed to the anti-inflammatory and immuno- The patients had received previous anti-inflammatory
modulatory functions of MSCs [162]. Furthermore, an and/or antiviral drugs, including lopinavir/ritonavir, ste-
+
+
increase in CD14 CD11c CD11b mid regulatory DC roids, tocilizumab and/or hydroxychloroquine, among
population has been observed [162]. Leng et al. demon- others. Thirteen patients have been enrolled in the trial
6
strated that MSCs modulate the lung microenvironment and have received two IV doses of AT-MSC 0.98 × 10 per
by protecting or rejuvenating alveolar epithelial cells, re- kg of body weight, 3 days apart. The treatment has been
ducing fibrosis, and enhancing pulmonary function followed by a reduction in inflammatory parameters (CRP,
[162]. RNA-seq analysis for the transplanted MSCs in ferritin, LDH, IL-6) as well as increase in B-lymphocytes
+
+
COVID-19 patients showed that the transplanted MSCs (67%) and CD4 and CD8 (100%) T lymphocytes). Re-
do not express ACE2 or TMPRSS2, indicating that markably, a reduction of D-dimer and fibrinogen 5 days
MSCs cannot be infected with COVID-19; however, they after the first dose of AT-MSCs has been observed in
express high levels of anti-inflammatory and paracrine most patients, and the patients do not develop a thrombo-
factors, such as HGF, FGF, EGF, TGF-β, GAL, LIF, embolic event [169, 170].
NOA1, VEGF, NGF, and BDNF. Also, the transplanted Furthermore, a recent clinical trial has been employed
MSCs express high levels of AT2-specific surfactant pro- using MSC-derived exosomes. A prospective nonrando-
teins, SPA and SPC, suggesting that the MSCs may dif- mized open-label cohort study by Sengupta et al. has
ferentiate into AT2 cells [162]. evaluated the safety and efficacy of exosomes (ExoFlo™)
Another recently published study has tested the safety obtained from allogeneic BM-MSCs as treatment for se-
and efficacy of allogeneic AT-MSCs in 13 COVID-19 vere COVID-19. A total of 24 patients have received 15
adult patients under invasive mechanical ventilation [169]. ml of ExoFlo™. The treatment resulted in significant